Rifaximin
Amorphous rifaximin, methods of making it, and pharmaceutical compositions containing it. Also described are methods of converting amorphous rifaximin to crystalline rifaximin and vice versa.
1. A process for manufacturing amorphous rifaximin comprising:
a) reacting Rifamycin S with 2-amino-4-picoline in the presence of a suitable solvent
b) adding iodine dissolved in suitable solvent to the above reaction mass followed by a reducing agent
c) adjusting the pH of the reaction mass between 1.5-2.5 under stirring
d) extracting with water immiscible organic solvent and concentrating the organic layer to form a residue
e) stripping the residue obtained in step d) with a water immiscible solvent or mixture of water immiscible solvents to residue
f) stirring the residue obtained in step e) with a water immiscible solvent or mixtures thereof to get a solid
g) filtering the solid and washing the same solvent/s and
h) drying the solid at a temperature below 40° C.
2. A process according to claim 1 , wherein the solvent or solvents used in step (e) is selected from one or more of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate.
3. A process according to claim 1 or 2 , wherein the solvents in step (f) are selected from at least two of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate.
4. A process for converting amorphous rifaximin to crystalline γ form rifaximin, said process comprising combining the amorphous rifaximin with a mixture of an organic acid and water, then drying the rifaximin mixture at a temperature from 100 to 110° C. to yield γ form rifaximin.
5. A process according to claim 4 , wherein the organic acid is acetic acid or formic acid.
6. A process according to claim 4 or 5 , wherein prior to combining the amorphous rifaximin with the organic acid/water mixture, the rifaximin is dissolved in an organic solvent at 40-60° C., combined with water, allowed to cool, and filtered to produce a rifaximin residue which is combined with the organic acid and water.
7. A process for converting amorphous rifaximin to crystalline β form rifaximin, said process comprising combining the amorphous rifaximin with a mixture of water miscible organic solvent and water, then drying the rifaximin mixture at a temperature from 80 to 110° to yield β form rifaximin.
8. A process according to claim 7 , wherein the water-miscible solvent is at least one of acetone, acetonitrile, and one or more C 1-4 alcohols.
9. A process according to claim 7 or 8 , wherein prior to combining the amorphous rifaximin with the mixture of organic solvent and water, the amorphous rifaximin is dissolved in an organic solvent at 40-60° C., combining with water, allowed to cool, and filtered to produce a rifaximin residue which is combined with the water miscible solvent and water.
10. A process for converting a crystalline form of rifaximin to an amorphous form of rifaximin, said process comprising dissolving the crystalline rifaximin in a suitable solvent, filtering the solution, washing the filtrate with a suitable solvent, and concentrating the residue at 40-60° C. to form a rifaximin residue followed by the steps of:
(a) stripping rifaximin residue with a water-immiscible solvent, or a mixture of water-immiscible solvents;
(b) stirring the residue obtained in step (a) with water immiscible solvents or mixtures thereof to get a solid
(c) filtering the solid and washing with the same solvent/s and
(d) drying the solid at a temperature below 40° C.
11. A process according to claim 10 , wherein the solvent used in step (b) is selected from one or more of: n-heptane, n-hexane, di-isopropyl ether, dichloromethane, dichloroethylene, chloroform and ethyl acetate.